Transfer hydrogenation process and catalyst

ABSTRACT

A catalytic transfer hydrogenation process is provided. The catalyst employed in the process is a metal hydrocarbyl complex which is coordinated to defined bidentate ligands substituted with at least one group selected from an optionally substituted sulphonated hydrocarbyl group, a sulphonated perhalogenated hydrocarbyl group, or an optionally substituted sulphonated heterocyclyl group. Preferred metals include rhodium, ruthenium and iridium. Preferred bidentate ligands are diamines and aminoalcohols, particularly those comprising chiral centres. The hydrogen donor is advantageously a secondary alcohol or a mixture of triethylamine and formic acid. The process can be employed to transfer hydrogenate ketones and imines, which are preferably prochiral. Catalysts for use in such a process are also provided.

[0001] The present invention relates to transfer hydrogenation andencompasses processes for transfer hydrogenation, e.g. for producingoptically active compounds and catalysts for use in such processes.

[0002] Numerous catalysts (generally comprising a transition metal) areknown for effecting transfer hydrogenation. The following disclosuresare of relevance.

[0003] (1) Noyori et al; J.A.C.S., 1995, 117 7562-7563: which disclosesthat use ofchloro-ruthenium-mesitylene-N-monotosyl-1,2-diphenylethlyenediamine ascatalyst in the transfer hydrogenation of acetophenone to1-phenylethanol by propan-2-ol gave up to a 95% yield of product having97% entantiomeric excess. Similar results were obtained starting fromother alkylaryl ketones.

[0004] (2) Noyori et al: J. Chem.Soc.Chem, Commun, 1996, 233-234: whichdiscloses catalysts similar to those of (1) above but containing otheralkylbenzene ligands and various beta-amino alcohols in place ofdiphenylethylenediamine. The preferred arene ligand washexamethylbenzene.

[0005] (3) Our earlier WO98/42643 which discloses transfer hydrogenationcatalysts incorporating an optionally substituted cyclopentadienyl groupco-ordinated or otherwise bonded to a metal (e.g. ruthenium, rhodium oriridium) capable of catalysing transfer hydrogenation. The hydrogenationof compound containing carbon-carbon, carbon-nitrogen, carbon-oxygen andcarbon-sulphur double bonds is disclosed.

[0006] (4) Our earlier WO00/18708 discloses transfer hydrogenation ofiminium salts (including protanated imine salts and quaternary iminesalts) using catalysts of the type disclosed in (1) to (3).

[0007] The catalysts used in (1)-(4) whilst being effective for transferhydrogenation have the disadvantage that they are difficult to recoverfrom the product mixture.

[0008] This gives rise to a number of problems. Firstly, the catalystsare relatively expensive and the fact that at least a portion of thecatalysts may not be recoverable adds to the expense of thehydrogenation process. Secondly, the fact that catalyst is present inthe final product may prevent application of the hydrogenation processto the production of pharmaceutical and veterinary products sinceadministration of the catalyst residue to humans or animals isundesirable.

[0009] It is therefore an object of the present invention to obviate ormitigate the abovementioned disadvantage.

[0010] According to a first aspect of the present invention there isprovided a process for the transfer hydrogenation of an organic compoundhaving a carbon-carbon or carbon-heteroatom double bond, said processcomprising reacting said organic compound with a hydrogen donor in thepresence of a catalyst having the general formula:

[0011] in which:

[0012] R¹⁸ represents an optionally substituted hydrocarbyl orperhalogenated hydrocarbyl ligand;

[0013] A represents —NR¹⁹—, —NR²⁰—, —NHR¹⁹, —NR¹⁹R²⁰ or —NR²⁰R²¹ whereR¹⁹ is H, C(O)R²¹, SO₂R²¹, C(O)NR²¹R²⁵, C(S)NR²¹R²⁵, C(═NR²⁵)SR²⁶ orC(═NR²⁵)OR²⁶, R²⁰ and R²¹ each independently represents an optionallysubstituted hydrocarbyl, perhalogenated hydrocarbyl or an optionallysubstituted heterocyclyl group, and R²⁵ and R²⁶ are each independentlyhydrogen or a group as defined for R²¹;

[0014] B represents —O—, —OH, OR²², —S—, —SH, SR²², —NR²²—, —NR²³—,—NHR²³, —NR²²R²³, —NR²²R²⁴, —PR²²— or —PR²²R²⁴ where R²³ is H, C(O)R²⁴,SO₂R²⁴, C(O)NR²⁴R²⁷, C(S)NR²⁴R²⁷, C(═NR²⁷)SR²⁸ or C(═NR²⁷)OR²⁸, R²² andR²⁴ each independently represents an optionally substituted hydrocarbyl,perhalogenated hydrocarbyl or an optionally substituted heterocyclylgroup, and R²⁷ and R²⁸ are each independently hydrogen or a group asdefined for R²⁴;

[0015] E represents a linking group;

[0016] M represents a metal capable of catalysing transferhydrogenation; and

[0017] Y represents an anionic group, a basic ligand or a vacant site;

[0018] provided that when Y is not a vacant site that at least one of Aor B carries a hydrogen atom, characterised in that at least one of saidgroups R²⁰ to R²² or R²⁴ to R²⁸ is present in the form of an optionallysubstituted sulphonated hydrocarbyl group, a sulphonated perhalogenatedhydrocarbyl group, or an optionally substituted sulphonated heterocyclylgroup.

[0019] According to a second aspect of the present invention there isprovided catalysts as defined in the preceding paragraph.

[0020] As used herein (and unless the context otherwise requires) theterm “sulphonated” is intended to cover the presence of the sulphonicacid moiety (—SO₃H) and salts thereof. Alkali metal (particularly sodiumand potassium) sulphonates are preferred examples of sulphonate groups.Furthermore the enhanced solubility of the ligands (as provided by thepolar sulphonate group) gives rise to the possibility of conductinghydrogenation reactions in water, other polar solvents, biphasic systemsand in support polar phase catalysis. Alternatively, the sulphonategroup may be present in the form of an anhydride (e.g. partially derivedfrom a CO₂H group).

[0021] The catalytic species is believed to be substantially asrepresented in the above formula. It may be introduced on a solidsupport.

[0022] The transfer hydrogenation process may for example be conductedas a homogenous reaction of the type disclosed in (1) to (4) above andthe hydrogenated product obtained by standard make-up procedures such asextracting the product mixture with water (e.g. after dilution of themixture with diethyl ether) and then drying the organic layer over, forexample, magnesium sulphate followed by filtration and evaporation ofsolvent.

[0023] The presence of the polar sulphonate group does however give riseto the possibility of effecting the reaction and/or product recovery invarious ways.

[0024] Thus, for example, at the end of the reaction there may be addedto the product mixture an ion exchange resin so that the catalystbecomes immobilised on the resin by virtue of its sulphonate group. Theproduct mixture may then be decanted from the resin and the productrecovered with minimal or no catalyst residue. Accordingly, a furtheraspect of the present invention comprises a process of the first aspectof the present invention, further comprising an additional step ofadding an ion exchange resin after reacting the organic compound withthe hydrogen donor in the presence of the catalyst.

[0025] Alternatively the catalyst may be used as a “supported liquidphase catalyst” which comprises a support (e.g. beads) coated with athin film of the catalyst dissolved in water or other polar solvent. Thetransfer hydrogenation phase is then effected by providing the supportin the bulk organic phase (containing the hydrogen donor and thesubstrate to be hydrogenated) of the reaction. The base that is normallyrequired for the reaction may be provided in either the film on thebeads or dissolved in the bulk organic phase. Hydrogenated product willbe produced in the bulk organic phase which, at the end of the reaction,may be decanted from the solid phase for recovery of the product. Thisprocedure has the advantage of ensuring no or minimal catalyst residuein the first product.

[0026] As stated above, the catalyst incorporates at least one group R²⁰to R²² or R²⁴ to R²⁸ which is an optionally substituted sulphonatedhydrocarbyl, sulphonated perhalogenated hydrocarbyl or optionallysubstituted sulphonated heterocyclyl group. The catalyst may incorporateat least one further R²⁰ to R²² or R²⁴ to R²⁸ group in the form of anoptionally substituted hydrocarbyl, perhalogenated hydrocarbyl oroptionally substituted heterocyclyl group where the substituent(s) ifpresent is/are other than sulphonate group(s). For convenience in thefollowing description reference will be made to the types ofhydrocarbyl, perhalogenated hydrocarbyl and heterocyclyl groups whichmay be used for R²⁰ to R²² or R²⁴ to R²⁸ (as well as groups R¹⁻¹⁷), itbeing understood that the sulphonated form of R²⁰ to R²² or R²⁴ to R²⁸may be a sulphonated form of the moieties described therefore.

[0027] The process of the invention effects hydrogenation of acarbon-carbon or carbon-heteroatom double bond in an organic compound.Examples of the heteroatoms that may form part of the double bondinclude oxygen, sulphur and nitrogen. Examples of organic compounds thatmay be hydrogenated by the process of the invention are of formula I:

[0028] wherein:

[0029] X represents O, S, CR³R⁴, NR⁵, (NR⁶R⁷)⁺Q⁻, N⁺R⁸—O⁻, (NR⁹OR¹⁰)⁺Q⁻,NNR¹²R¹³, NNR¹²SO₂R¹⁶, NNR¹²COR¹⁷, (NR¹¹NR¹²R¹³)⁺Q⁻,(NR¹¹NR¹²C(═NR¹⁴)R¹⁵)⁺Q⁻, (NR¹¹NR¹²SO₂R¹⁶)⁺Q⁻, (NR¹¹NR¹²COR¹⁷)⁺Q⁻,NP(O)R¹⁵R¹⁶, NS(O)R¹⁵ or NSO₂R¹⁵.

[0030] Q represents a monovalent anion;

[0031] R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ R¹², R¹³ and R¹⁴each independently represents a hydrogen atom, an optionally substitutedhydrocarbyl, a perhalogenated hydrocarbyl or an optionally substitutedheterocyclyl group, one or more of R¹ and R², R¹ and R³, R¹ and R⁵, R¹and R⁶, R¹ and R⁸, R¹ and R⁹, R¹ and R¹¹, R¹ and R¹², R² and R⁴, R² andR⁷, R² and R¹⁰, R³ and R⁴, R⁶ and R⁷, R⁹ and R¹⁰, R¹¹ and R¹², and R¹²and R¹³ optionally being linked in such a way as to form an optionallysubstituted ring(s); and R¹⁵, R¹⁶ and R¹⁷ each independently representsan optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl oran optionally substituted heterocyclyl group;

[0032] Hydrocarbyl groups which may be represented by R¹⁻¹⁷, R²⁰⁻²² andR²⁴⁻²⁸ independently include alkyl, alkenyl and aryl groups, and anycombination thereof, such as aralkyl and alkaryl, for example benzylgroups.

[0033] Alkyl groups which may be represented by R¹⁻¹⁷, R²⁰⁻²² and R²⁴⁻²⁸include linear and branched alkyl groups comprising up to 20 carbonatoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5carbon atoms. When the alkyl groups are branched, the groups oftencomprise up to 10 branched chain carbon atoms, preferably up to 4branched chain atoms. In certain embodiments, the alkyl group may becyclic, commonly comprising from 3 to 10 carbon atoms in the largestring and optionally featuring one or more bridging rings. Examples ofalkyl groups which may be represented by R¹⁻¹⁷, R²⁰⁻²² and R²⁴⁻²⁸include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl andcyclohexyl groups.

[0034] Alkenyl groups which may be represented by R¹⁻¹⁷, R²⁰⁻²² andR²⁴⁻²⁸ include C₂₋₂₀, and preferably C₂₋₆ alkenyl groups. One or morecarbon-carbon double bonds may be present. The alkenyl group may carryone or more substituents, particularly phenyl substituents. Examples ofalkenyl groups include vinyl, styryl and indenyl groups. When either ofR¹ or R² represents an alkenyl group, a carbon-carbon double bond ispreferably located at the position β to the C═X moiety. When either ofR¹ or R² represents an alkenyl group, the compound of formula (1) ispreferably an α,β-unsaturated iminium compound.

[0035] Aryl groups which may be represented by R¹⁻¹⁷, R²⁰⁻²² and R²⁴⁻²⁸may contain 1 ring or 2 or more fused rings which may includecycloalkyl, aryl or heterocyclic rings. Examples of aryl groups whichmay be represented by R¹⁻¹⁷, R²⁰⁻²² and R²⁴⁻²⁸ include phenyl, tolyl,fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl,naphthyl and ferrocenyl groups.

[0036] Perhalogenated hydrocarbyl groups which may be represented byR¹⁻¹⁷, R²⁰⁻²² and R²⁴⁻²⁸ independently include perhalogenated alkyl andaryl groups, and any combination thereof, such as aralkyl and alkarylgroups. Examples of perhalogenated alkyl groups which may be representedby R¹⁻¹⁷, R²⁰⁻²² and R²⁴⁻²⁸ include —CF₃ and —C₂F₅.

[0037] Heterocyclic groups which may be represented by R¹⁻¹⁷, R²⁰⁻²² andR²⁴⁻²⁸ independently include aromatic, saturated and partiallyunsaturated ring systems and may constitute 1 ring or 2 or more fusedrings which may include cycloalkyl, aryl or heterocyclic rings. Theheterocyclic group will contain at least one heterocyclic ring, thelargest of which will commonly comprise from 3 to 7 ring atoms in whichat least one atom is carbon and at least one atom is any of N, O, S orP. When either of R¹ or R² represents or comprises a heterocyclic group,the atom in R¹ or R² bonded to the C═X group is preferably a carbonatom. Examples of heterocyclic groups which may be represented by R¹⁻¹⁷,R²⁰⁻²² and R²⁴⁻²⁸ include pyridyl, pyrimidyl, pyrrolyl, thiophenyl,furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl and triazoyl groups.

[0038] When any of R¹⁻¹⁷, R²⁰⁻²² and R²⁴⁻²⁸ is a substituted hydrocarbylor heterocyclic group, the substituent(s) should be such so as not toadversely affect the rate or stereoselectivety of the reaction. Optionalsubstituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl,hydrocarbyl, perhalogenated hydrocarbyl, heterocyclyl, hydrocarbyloxy,mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates,amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groupsare as defined for R¹ above. One or more substituents may be present.

[0039] When any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R⁶, R¹ andR⁸, R¹ and R⁹, R¹ and R¹¹, R¹ and R¹², R² and R⁴, R² and R⁷, R² and R¹⁰,R³ and R⁴, R⁶ and R⁷, R⁹ and R¹⁰, R¹¹ and R¹², and R¹² and R¹³ arelinked in such a way that when taken together with either the carbonatom and/or atom X of the compound of formula (1) that a ring is formed,it is preferred that these be 5, 6 or 7 membered rings. The rings formedin this way may additionally be fused to each other or to other ringsystems. Examples of rings which may be so formed include:

[0040] wherein X is as defined above and the rings may be optionallysubstituted or may be fused to other rings.

[0041] In certain preferred embodiments, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ R¹⁵, R¹⁶ and R¹⁷ are all independently C₁₋₆alkyl or are a combination of aryl, particularly phenyl, C₁₋₆ alkyl andC₆₋₁₀aralkyl. Substituents may be present, particularly substituentspara to the C═X group when one or more of R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is a phenyl group.

[0042] In especially preferred embodiments, R⁴, R⁵, R⁶, or R⁸ are C₁₋₆alkyl or C₆₋₁₀aralkyl, especially methyl, benzyl or PhCHCH₃.

[0043] Compounds of formula (1) where X is represented by NR⁵ or(NR⁶R⁷)⁺Q⁻, include imines or iminium salts. Where a compound of formula(1) is an imine, it may optionally be converted to an iminium salt.Iminium salts are preferred over imines. Preferred iminium salts arerepresented by compounds of formula (1) in which X is (NR⁶R⁷)⁺Q⁻ suchthat either R⁶ or R⁷ are hydrogen but that R⁶ and R⁷ are not identical.When the compound of formula (1) is an iminium salt, an anionrepresented by Q⁻ is present.

[0044] Anions which may be represented by Q⁻ include halides, optionallysubstituted arylsulphonates, such as optionally substituted phenyl andnapthyl sulphonates, optionally substituted alkylsulphonates includinghalogenated alkylsulphonates, such as C₁₋₂₀alkylsulphonates, optionallysubstituted carboxylates, such as C₁₋₁₀ alkyl and aryl carboxylates,ions derived from the polyhalogenation of boron, phosphorous orantimony, and other common inorganic ions for example perchlorate.Examples of anions which may be present are bromide, chloride, iodide,hydrogen sulphate, tosylate, formate, acetate, tetrafluoroborate,hexafluorophosphate, hexafluoroantimonate, perchlorate,trifluoromethanesulphonate and trifluoroacetate. Preferred anionsinclude bromide, chloride, iodide, formate and trifluoroacetate,particularly preferred anions include iodide, formate andtrifluoroacetate.

[0045] In certain preferred embodiments, X is a group of formula(NR⁶R⁷)⁺Q⁻ and R¹ and R⁶ are linked in such a way that when takentogether with the carbon atom and the nitrogen atom of the C═X group ofthe compound of formula (1) that a 5, 6 or 7 membered ring is formed, R⁷is C₁₋₆ alkyl or C₆₋₁₀aralkyl, especially methyl, benzyl or PhCHCH₃, andR² is optionally substituted hydrocarbyl, preferably C₁₋₆ alkyl, oroptionally substituted phenyl especially methoxy, hydroxy or fluorosubstituted phenyl. The 5, 6 or 7 membered ring formed by linking R¹ andR⁶ optionally may be fused to another ring system, preferably abenzenoid system which may be substituted, preferred substituentsinclude hydroxy, methoxy and fluoro.

[0046] In certain preferred embodiments X is O so that the compound ofthe formula (I) is a ketone.

[0047] Most advantageously, the compound of formula (1) is prochiral,such that the hydrogenated product comprises a chiral atom to which R¹,R² and X are each bonded. Such an asymmetric transfer hydrogenationprocess forms an especially preferred aspect of the present invention.Most commonly, when the compound of formula (1) is prochiral, R¹ and R²are different, and neither is hydrogen. Advantageously, one of R¹ and R²is aliphatic and the other is aryl or heterocyclyl.

[0048] Examples of compounds of formula (1) include acetophenone,4-chloroacetophenone, 4-methoxyacetophenone,4-trifluoromethylacetophenone, 4-nitroacetophenone, 2-chloroacetophenoneand acetophenone benzylimine.

[0049] Further examples of compounds of formula (1) include:

[0050] wherein R² and R⁷ are as described above and G¹, G² and G³ areindependently hydrogen, chloro, bromo, fluoro, iodo, cyano, nitro,hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogenated hydrocarbyl,heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino,hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamidogroups wherein the hydrocarbyl groups are as defined for R¹ above.

[0051] Hydrogen donors include hydrogen, primary and secondary alcohols,primary and secondary amines, carboxylic acids and their esters andamine salts, readily dehydrogenatable hydrocarbons, clean reducingagents, and any combination thereof.

[0052] Primary and secondary alcohols which may be employed as hydrogendonors comprise commonly from 1 to 10 carbon atoms, preferably from 2 to7 carbon atoms, and more preferably 3 or 4 carbon atoms. Examples ofprimary and secondary alcohols which may be represented as hydrogendonors include methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol,butan-2-ol, cyclopentanol, cyclohexanol, benzylalcohol, and menthol.When the hydrogen donor is an alcohol, secondary alcohols are preferred,especially propan-2-ol and butan-2-ol.

[0053] Primary and secondary amines which may be employed as hydrogendonors comprise commonly from 1 to 20 carbon atoms, preferably from 2 to14 carbon atoms, and more preferably 3 or 8 carbon atoms. Examples ofprimary and secondary amines which may be represented as hydrogen donorsinclude ethylamine, propylamine, isopropylamine, butylamine,isobutylamine, hexylamine, diethylamine, dipropylamine,di-isopropylamine, dibutylamine, di-isobutylamine, dihexylamine,benzylamine, dibenzylamine and piperidine. When the hydrogen donor is anamine, primary amines are preferred, especially primary aminescomprising a secondary alkyl group, particularly isopropylamine andisobutylamine.

[0054] Carboxylic acids or their esters which may be employed ashydrogen donors comprise commonly from 1 to 10 carbon atoms, preferablyfrom 1 to 3 carbon atoms. In certain embodiments, the carboxylic acid isadvantageously a beta-hydroxy-carboxylic acid. Esters may be derivedfrom the carboxylic acid and a C₁₋₁₀ alcohol. Examples of carboxylicacids which may be employed as hydrogen donors include formic acid,lactic acid, ascorbic acid and mandelic acid. The most preferredcarboxylic acid is formic acid. In certain preferred embodiments, when acarboxylic acid is employed as hydrogen donor, at least some of thecarboxylic acid is preferably present as salt, preferably an amine,ammonium or metal salt. Preferably, when a metal salt is present themetal is selected from the alkali or alkaline earth metals of theperiodic table, and more preferably is selected from the group Ielements, such as lithium, sodium or potassium. Amines which may be usedto form such salts include both aromatic and non-aromatic amines, alsoprimary, secondary and tertiary amines and comprise typically from 1 to20 carbon atoms. Tertiary amines, especially trialkylamines, arepreferred. Examples of amines which may be used to form salts includetrimethylamine, triethylamine, di-isopropylethylamine and pyridine. Themost preferred amine is triethylamine. When at least some of thecarboxylic acid is present as an amine salt, particularly when a mixtureof formic acid and triethylamine is employed, the mole ratio of acid toamine is between 1:1 and 50:1 and preferably between 1:1 and 10:1, andmost preferably about 5:2. When at least some of the carboxylic acid ispresent as a metal salt, particularly when a mixture of formic acid anda group I metal salt is employed, the mole ratio of acid to metal ionspresent is between 1:1 and 50:1 and preferably between 1:1 and 10:1, andmost preferably about 2:1. The ratios of acid to salts may be maintainedduring the course of the reaction by the addition of either component,but usually by the addition of the carboxylic acid.

[0055] Readily dehydrogenatable hydrocarbons which may be employed ashydrogen donors comprise hydrocarbons which have a propensity toaromatise or hydrocarbons which have a propensity to form highlyconjugated systems. Examples of readily dehydrogenatable hydrocarbonswhich may be employed by as hydrogen donors include cyclohexadiene,cyclohexene, tetralin, dihydrofuran and terpenes.

[0056] Clean reducing agents which may be represented as hydrogen donorscomprise reducing agents with a high reduction potential, particularlythose having a reduction potential relative to the standard hydrogenelectrode of greater than about −0.1 eV, often greater than about −0.5eV, and preferably greater than about −1 eV. Examples of clean reducingagents which may be represented as hydrogen donors include hydrazine andhydroxylamine.

[0057] The most preferred hydrogen donors are propan-2-ol, butan-2-ol,triethylammonium formate and a mixture of triethylammonium formate andformic acid. However, in certain embodiments when the compound ofFormula (1) is a protonated imminium salt, it may be desirable to employa hydrogen donor which is not a carboxylic acid or a salt thereof.

[0058] The optionally substituted hydrocarbyl or perhalogenatedhydrocarbyl ligand which may be represented by R¹⁸ includes optionallysubstituted aryl, alkenyl and cyclopentadienyl ligands.

[0059] Optionally substituted aryl ligands which may be represented byR¹⁸ may contain 1 ring or 2 or more fused rings which includecycloalkyl, aryl or heterocyclic rings. The ligand may comprise a 6membered aromatic ring. The ring or rings of the aryl ligand are oftensubstituted with hydrocarbyl groups. The substitution pattern and thenumber of substituents will vary and may be influenced by the number ofrings present, but often from 1 to 6 hydrocarbyl substituent groups arepresent, preferably 2, 3 or 6 hydrocarbyl groups and more preferably 6hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl,ethyl, iso-propyl, menthyl, neomenthyl and phenyl. Particularly when thearyl ligand is a single ring, the ligand is preferably benzene or asubstituted benzene. When the ligand is a perhalogenated hydrocarbyl,preferably it is a polyhalogenated benzene such as hexachlorobenzene orhexafluorobenzne. When the hydrocarbyl substituents contain enantiomericand/or diastereomeric centres, it is preferred that the enantiomericallyand/or diastereomerically purified forms of these are used. Benzene,p-cymyl, mesitylene and hexamethylbenzene are especially preferredligands having a 6 membered aromatic ring.

[0060] Optionally substituted alkenyl ligands which may be representedby R¹⁸ include C₂₋₃₀, and preferably C₅₋₁₂, alkenes or cycloalkenes withpreferably two or more carbon-carbon double bonds, preferably only twocarbon-carbon double bonds. The carbon-carbon double bonds mayoptionally be conjugated to other unsaturated systems which may bepresent, but are preferably conjugated to each other. The alkenes orcycloalkenes may be substituted preferably with hydrocarbylsubstituents. When the alkene has only one double bond, the optionallysubstituted alkenyl ligand may comprise two separate alkenes. Preferredhydrocarbyl substituents include methyl, ethyl, iso-propyl and phenyl.Examples of optionally substituted alkenyl ligands includecyclo-octa-1,5-diene and 2,5-norbornadiene.

[0061] It is however particularly preferred that R¹⁸ is an optionallysubstituted cyclopentadienyl group.

[0062] Optionally substituted cyclopentadienyl group which may berepresented by R¹⁸ include particularly ones capable of eta-5 bonding.The cyclopentadienyl group is often substituted with from 1 to 5hydrocarbyl groups, preferably with 3 to 5 hydrocarbyl groups and morepreferably with 5 hydrocarbyl groups. Preferred hydrocarbyl substituentsinclude methyl, ethyl and phenyl. When the hydrocarbyl substituentscontain enantiomeric and/or diastereomeric centres, it is preferred thatthe enantiomerically and/or diastereomerically purified forms of theseare used. Examples of optionally substituted cyclopentadienyl groupsinclude cyclopentadienyl, pentamethyl-cyclopentadienyl,pentaphenylcyclopentadienyl, tetraphenylcyclopentadienyl,ethyltetramethylpentadienyl, menthyltetraphenylcyclopentadienyl,neomenthyl-tetraphenylcyclopentadienyl, menthylcyclopentadienyl,neomenthylcyclopentadienyl, tetrahydroindenyl, menthyltetrahydroindenyland neomenthyltetrahydroindenyl groups. Pentamethylcyclopentadienyl isespecially preferred.

[0063] It is particularly preferred that R¹⁸ is an optionallysubstituted cyclopentadienyl group.

[0064] When either A or B is an amide group represented by —NR¹⁹—,—NHR¹⁹, NR¹⁹R²⁰, —NR²³—, —NHR²³ or NR²²R²³ wherein R²⁰ and R²¹ are ashereinbefore defined, and where R¹⁹ or R²³ is an acyl group representedby —C(O)R²¹ or —C(O)R²⁴, R²¹ and R²⁴ independently are often linear orbranched sulphonated C₁₋₇alkyl, sulphonated C₁₋₈-cycloalkyl orsulphonated aryl, for example sulphonated phenyl. Examples ofsulphonated acyl groups which may be represented by R¹⁹ or R²³ includesulphonated benzoyl, acetyl and halogenoacetyl groups.

[0065] When either A or B is present as a sulphonamide group representedby —NR¹⁹—, —NHR¹⁹, NR¹⁹R²⁰, —NR²³—, —NHR²³ or NR²²R²³ wherein R²⁰ andR²² are as hereinbefore defined, and where R¹⁹ or R²³ is a sulphonylgroup represented by —S(O)₂R²¹ or —S(O)₂R²⁴, R²¹ and R²⁴ independentlyare often linear or branched sulphonated C₁₋₈alkyl, sulphonatedC₁₋₈cycloalkyl or sulphonated aryl, for example sulphonated phenyl.Preferred sulphonyl groups include sulphoanted derivatives ofmethanesulphonyl, trifluoromethanesulphonyl and especiallyphenylsulphonyl groups and naphthylsulphonyl groups.

[0066] When either of A or B is present as a group represented by—NR¹⁹—, —NHR¹⁹, NR¹⁹R²⁰, —NR²³—, —NHR²³ or NR²²R²⁴ wherein R²⁰ and R²³are as hereinbefore defined, and where R¹⁹ or R²³ is a group representedby C(O)NR²¹R²⁵, C(S)NR²¹R²⁵, C(═NR²⁵)SR²⁶, C(═NR²⁵)OR²⁶, C(O)NR²⁴R²⁷,C(S)NR²⁴R²⁷, C(═NR²⁷)SR²⁸ or C(═NR²⁷)OR²⁸, R²¹ and R²⁴ independently areoften linear or branched sulphonated C₁₋₈alkyl, such as methyl, ethyl,isopropyl, C₁₋₈cycloalkyl or sulphonated aryl, for example phenyl,groups and R²²⁻²⁵ are often each independently hydrogen or linear orbranched C₁₋₈alkyl, such as methyl, ethyl, isopropyl, sulphonatedC₁₋₈cycloalkyl or aryl, for example phenyl, groups.

[0067] When B is present as a group represented by —OR²², —SR²², —PR²²—or —PR²²R²⁴, R²² and R²⁴ independently are often linear or branchedC₁₋₈alkyl, such as methyl, ethyl, isopropyl, C₁₋₈cycloalkyl or aryl, forexample phenyl.

[0068] It will be recognised that the precise nature of A and B will bedetermined by whether A and/or B are formally bonded to the metal or arecoordinated to the metal via a lone pair of electrons.

[0069] It is particularly preferred in accordance with the inventionthat A is a group of the formula —NHR¹⁹ or —NR¹⁹— where R¹⁹ isrepresented by the group —SO₂R²¹ in which R²¹ is an optionallysubstituted sulphonated hydrocarbyl group, sulphonated perhalogenatedhydrocarbyl group or optionally substituted sulphonated heterocyclylgroup. Most preferably R²¹ is a sulphonated phenyl group having nsulphonate groups where n is 1 to 5. When n is 1 to 4 the sulphonategroups may be present in any substitution pattern on the aromatic ring.In the particular case where n=1 then the sulphonate group may be ortho,meta or para to the sulphonamide group.

[0070] B is preferably-NH₂ or ═NH═.

[0071] The groups A and B are connected by a linking group E. Thelinking group E achieves a suitable conformation of A and B so as toallow both A and B to bond or coordinate to the metal, M. A and B arecommonly linked through 2, 3 or 4 atoms. The atoms in E linking A and Bmay carry one or more substituents. The atoms in E, especially the atomsalpha to A or B, may be linked to A and B, in such a way as to form aheterocyclic ring, preferably a saturated ring, and particularly a 5, 6or 7-membered ring. Such a ring may be fused to one or more other rings.Often the atoms linking A and B will be carbon atoms. Preferably, one ormore of the carbon atoms linking A and B will carry substituents inaddition to A or B. Substituent groups include those which maysubstitute R¹, as defined above. Advantageously, any such substituentgroups are selected to be groups which do not coordinate with the metal,M. Preferred substituents include halogen, cyano, nitro, sulphonyl,hydrocarbyl, perhalogenated hydrocarbyl and heterocyclyl groups asdefined above. Most preferred substituents are C₁₋₆ alkyl groups, andphenyl groups. Most preferably, A and B are linked by two carbon atoms,and especially an optionally substituted ethyl moiety. When A and B arelinked by two carbon atoms, the two carbon atoms linking A and B maycomprise part of an aromatic or aliphatic cyclic group, particularly a5, 6 or 7-membered ring. Such a ring may be fused to one or more othersuch rings. Particularly preferred are embodiments in which E representsa 2 carbon atom separation and one or both of the carbon atoms carriesan optionally substituted aryl group as defined above or E represents a2 carbon atom separation which comprises a cyclopentane or cyclohexanering, optionally fused to a phenyl ring.

[0072] E preferably comprises part of a compound having at least onestereospecific centre. Where any or all of the 2, 3 or 4 atoms linking Aand B are substituted so as to define at least one stereospecific centreon one or more of these atoms, it is preferred that at least one of thestereospecific centres be located at the atom adjacent to either group Aor B. When at least one such stereospecific centre is present, it isadvantageously present in an enantiomerically purified state.

[0073] When B represents —O— or —OH, and the adjacent atom in E iscarbon, it is preferred that B does not form part of a carboxylic group.

[0074] Sulphonated compounds which may be represented by A-E-B, or fromwhich A-E-B may be derived by deprotonation, are often aminoalcohols ordiamines in which an or the amino nitrogen atom has bound (directly orindirectly) thereto a substituent incorporating a group R²⁰ to R²² orR²⁴ to R²⁸ in the form of an optionally substituted sulphonatedhydrocarbyl group, a sulphonated perhalogenated hydrocarbyl group or anoptionally substituted sulphonated heterocyclyl group. Examples ofaminoalcohols from which said N-substituted compound may be derivedincluding 4-aminoalkan-1-ols, 1-aminoalkan-4-ols, 3-aminoalkan-1-ols,1-aminoalkan-3-ols, and especially 2-aminoalkan-1-ols,1-aminoalkan-2-ols, 3-aminoalkan-2-ols and 2-aminoalkan-3-ols, andparticularly 2-aminoethanols or 3-aminopropanols. Further aminoalcoholsare 2-aminocyclopentanols and 2-aminocyclohexanols, preferably fused toa phenyl ring. Examples of diamines from which said N-substitutedcompounds may be derived include 1,4-diaminoalkanes, 1,3-diaminoalkanes,especially 1,2- or 2,3-diaminoalkanes and particularly ethylenediamines.Further diamines are 1,2-diaminocyclopentanes and1,2-diaminocyclohexanes, preferably fused to a phenyl ring. Theaminoalcohols or diamines are advantageously substituted, especially onthe linking group, E, by at least one alkyl group, such as a C₁₋₄-alkyl,and particularly a methyl, group or at least one aryl group,particularly a phenyl group.

[0075] In summary it is particularly preferred that E has two carbonatoms linking A and B, one or both of these atoms being optionallysubstituted. In certain preferred embodiments E is of the formula—CHR³⁰—CHR³¹— where R³⁰ and R³¹ are independently hydrogen or anoptionally substituted hydrocarbyl group.

[0076] In other preferred embodiments, E is a carbon-carbon bond that ispart of an optionally substituted cycloaliphatic ring, preferablycyclopentyl or cyclohexyl.

[0077] Examples of ligands from which compounds A-E-B may be derived areas follows:

[0078] in which:

[0079] W is —OH or —NH₂;

[0080] R³² is an aryl group having at least one —SO₃H or SO₃M¹(M¹=alkali metal) substituent and is further optionally substituted,e.g. with a carboxylic acid group which may, for example, be ortho tothe —SO₃H or —SO₃M¹ group and may lead to anhydride formulationtherewith. More preferably R³² is a phenyl group having one —SO₃H or—SO₃M¹ substituent; and

[0081] R³³, R³⁴ are independently optionally substituted hydrocarbylgroups or R³³ and R³⁴ are optionally linked in such a way as to definean optionally substituted ring, more preferably R³³ and R³⁴ areindependently phenyl or R³³ and R³⁴ are linked so as to define acyclohexyl ring.

[0082] Specific examples of aminoalcohols and diamines from which thesulphonated compounds A-E-B may be derived are:

[0083] Advantageously, certain ligands are prepared by oxidativecleavage of the corresponding di-sulphide.

[0084] Accordingly there is provided a process comprising reacting adi-sulphide of formula:

[0085] with an oxidant to produce a compound of formula:

[0086] wherein:

[0087] W is —OH or —NH₂;

[0088] R³² is an aryl group having at least one —SO₃H or SO₃M¹(M¹=alkali metal) substituent;

[0089] R³⁵ is an aryl group; and

[0090] R³³, R³⁴ are independently optionally substituted hydrocarbylgroups or R³³ and R³⁴ are optionally linked in such a way as to definean optionally substituted ring, more preferably R³³ and R³⁴ areindependently phenyl or R³³ and R³⁴ are linked so as to define acyclohexyl ring.

[0091] Preferably the substitution pattern of the aryl group R³² is suchthat the —SO₃H or SO₃M¹ (M¹=alkali metal) substituent is positioned parawith respect to the SO₂NH—CHR³⁴—CHR³³—W group. Corresponding a similarsubstitution pattern in R³⁵ is preferred.

[0092] Preferably the oxidant is alkaline hydrogen peroxide,particularly a mixture is sodium hydroxide solution and hydrogenperoxide solution.

[0093] Metals which may be represented by M include metals which arecapable of catalysing transfer hydrogenation. Preferred metals includetransition metals, more preferably the metals in Group VIII of thePeriodic Table, especially ruthenium, rhodium or iridium. When the metalis ruthenium it is preferably present in valence state II. When themetal is rhodium or iridium it is preferably present in valence state I.

[0094] Anionic groups which may be represented by Y include hydride,hydroxy, hydrocarbyloxy, hydrocarbylamino and halogen groups. Preferablywhen a halogen is represented by Y, the halogen is chloride. When ahydrocarbyloxy or hydrocarbylamino group is represented by Y, the groupmay be derived from the deprotonation of the hydrogen donor utilised inthe reaction.

[0095] Basic ligands which may be represented by Y include water, C₁₋₄alcohols, C₁₋₈ primary or secondary amines, or the hydrogen donor whichis present in the reaction system. A preferred basic ligand representedby Y is water.

[0096] Most preferably, the nature of A-E-B, R¹⁸ and Y are chosen suchthat the catalyst is chiral. When such is the case, an enantiomericallyand/or diastereomerically purified form is preferably employed. Suchcatalysts are most advantageously employed in asymmetric transferhydrogenation processes. In many embodiments, the chirality of thecatalyst is derived from the nature of A-E-B.

[0097] The process is carried out preferably in the presence of a base,especially when Y is not a vacant site. The pK_(a) of the base ispreferably at least 8.0, especially at least 10.0. Convenient bases arethe hydroxides, alkoxides and carbonates of alkali metals; tertiaryamines and quaternary ammonium compounds. Preferred bases are sodium2-propoxide and triethylamine. When the hydrogen donor is not an acid,the quantity of base used can be up to 5.0, commonly up to 3.0, often upto 2.5 and especially in the range 1.0 to 3.5, by moles of the catalyst.When the hydrogen donor is an acid, the catalyst may be contacted with abase prior to the introduction of the hydrogen donor. In such a case,the mole ratio of base to catalyst prior to the introduction of thehydrogen donor is often from 1:1 to 3:1, and preferably about 1:1.

[0098] Although gaseous hydrogen may be present, the process is normallyoperated in the absence of gaseous hydrogen since it appears to beunnecessary.

[0099] Advantageously, the process is carried out in the substantialabsence of carbon dioxide.

[0100] When the product(s) from dehydrogenation of the hydrogen donor isvolatile, for example boils at under 100° C., the removal of thisvolatile product is preferred. The removal can be accomplished bydistillation preferably at less than atmospheric pressure or by use ofinert gas sparging. When reduced pressure distillation is employed, thepressure is often no more than 500 mmHg, commonly no more than 200 mmHg,preferably in the range of from 5 to 100 mmHg, and most preferably from10 to 80 mmHg. When the product(s) from dehydrogenation of the hydrogendonor is a gaseous material, for example when formic acid is present asa hydrogen donor, the removal is most preferably accomplished by the useof inert gas sparging, with for example nitrogen.

[0101] Suitably the process is carried out at temperatures in the rangeof from minus 78 to plus 150° C., preferably from minus 20 to plus 110°C. and more preferably from minus 5 to plus 60° C. The initialconcentration of the substrate, a compound of formula (1), is suitablyin the range 0.05 to 1.0 and, for convenient larger scale operation, canbe for example up to 6.0 more especially 0.25 to 2.0, on a molar basis.The molar ratio of the substrate to catalyst is suitably no less than50:1 and can be up to 50000:1, preferably between 100:1 and 5000:1 andmore preferably between 200:1 and 2000:1. The hydrogen donor ispreferably employed in a molar excess over the substrate, especiallyfrom 5 to 20 fold or, if convenience permits, greater, for example up to500 fold. After reaction, the mixture is worked up by standardprocedures.

[0102] During the reaction a solvent may be present, preferably a polarsolvent, more preferably a polar aprotic solvent, for exampleacetonitrile, dimethylformamide or dichloromethane. Conveniently, thehydrogen donor may be the solvent when the hydrogen donor is liquid atthe reaction temperature, or it may be used in combination with adiluent. Usually it is preferred to operate in substantial absence ofwater, but water does not appear to inhibit the reaction. If thehydrogen donor or the reaction solvent is not miscible with water andthe desired product is water soluble, it may be desirable to have waterpresent as a second phase extracting the product, pushing theequilibrium and preventing loss of product optical purity as thereaction proceeds. The concentration of substrate may be chosen tooptimise reaction time, yield and enantiomeric excess.

[0103] The catalytic species is believed to be substantially asrepresented in the above formula. It may be employed as an oligomer ormetathesis product, on a solid support or may be generated in situ.

[0104] The catalyst can be made by reacting a metal aryl or alkenylhalide complex with a compound of formula A-E-B as defined above or aprotonated equivalent from which it may be derived, and, where Yrepresents a vacant site, reacting the product thereof with a base. Themetal aryl or alkenyl halide complex preferably has the formula[MR¹⁸Z₂]₂ when M is ruthenium (II) and has the formula [MR¹⁸Z]₂ when Mis iridium or rhodium (I), wherein R¹⁸ is as defined above, and Zrepresents a halide, particularly chloride.

[0105] For the preparation of the catalysts according to the presentinvention, a solvent is preferably present. Suitable reactiontemperatures are in the range 0-100° C., for example 20-70° C., oftengiving reaction times of 0.5-24.0 h. After reaction is complete, thecatalyst may if desired be isolated, but is more conveniently stored asthe solution or used soon after preparation. The solution can containthe hydrogen donor and this, if a secondary alcohol, may be present inor used as the solvent for step (a) and/or (b). The preparation andafter-handling should preferably be under an inert atmosphere, andparticularly in carbon dioxide and oxygen-free conditions.

[0106] The catalyst or catalyst solution is generally treated with baseeither just prior to use in a transfer hydrogenation reaction, or duringuse. This can be accomplished by adding base to the catalyst insolution, or to the compound of formula (1) in solution, or by additionto the transfer hydrogenation reaction.

[0107] Iminium salts can generally be obtained by known literaturemethods, for example the quaternisation of imines, such as by treatmentof imines with alkylating agents.

[0108] Transfer hydrogenation can be accomplished by transferring thesolution of catalyst to a solution of substrate, a compound of generalformula I. Alternatively a solution of substrate can be added to asolution of catalyst. Base may be pre-added to the catalyst solutionand/or the substrate solution, or can be added later. The hydrogen donorif not already present in the catalyst solution may be added to thesubstrate solution, or may be added to the reaction mixture.

[0109] The invention is illustrated by the following Examples.

[0110] The invention will be illustrated by the following non-limitingExamples. For convenience, the Examples are divided into two sections,viz a Ligand Synthesis Section in which Examples LS1-4 and LS18 describethe synthesis of various ligands embraced by the formula A-E-B describedabove and a “Catalyst Preparation and Hydrogenation” Section in whichExamples TH5-17 and describe preparation of catalysts with ligands assynthesised in Examples LS1-4 and transfer hydrogenation reactionsemploying these catalysts. Example TH19 describes a transferhydrogenation process wherein the catalyst is removed at he end ofreaction by treatment with ion exchange resins.

EXAMPLES Example LS 1 Preparation of Sodium (1S,2S)-1,2-diphenylethylenediamine-N-phenylsulfonyl-4-sulfonate (CB 3.016).

[0111]

[0112] (i) Synthesis of Sodium 4,4′-dithiobisbenzenesulfonate. (CB3.011)

[0113] Sodium 4,4′-dithiobisbenzenesulfonate (CB3.011) was synthesisedfollowing the protocol of Smith et. al (H. A Smith, G. Goughty, G Dorinj. Chem. Soc., 1964, 29, 1484-1488) with some minor modifications.Sulfanilic acid (47.5 g, 0.25 mol) and anhydrous sodium carbonate weredissolved in water (500 ml) by warming. The solution was cooled to 15°C. and sodium nitrite (18.5 g, 0.27 mol) in water (50 ml) was added. Themixture was poured slowly into conc. hydrochloric acid (52.5 ml, 0.64mol) and crushed ice (300 g) and the resulting suspension was stirredfor 15 minutes.

[0114] Sodium sulfide nonahydrate (65 g, 0.27 mol) and powdered sulfur(8.5 g, 0.27 mol) were dissolved in water (75 ml) at 100° C. A solutionof sodium hydroxide (10 g, 0.25 mol) in water (100 ml) was added and theresulting disodium disulfide solution was cooled to 0° C. (ice bath).The diazo solution was added over a period of 30 minutes, along with 50g of ice to keep the temperature below 5° C. The ice bath was removedand the reaction mixture was allowed to come to room temperature. After2 hours the evolution of nitrogen ceased and the reaction mixture wasacidified to pH 2 by addition of conc. hydrochloric acid. Theprecipitated sulfur was filtered off and the solution was concentratedby heating on a stirrer hotplate to a volume of ca. 500 ml. Aftercooling to r.t. the solution was neutralised with sodium hydroxidesolution (10% in water) and concentrated to 400 ml. The productcrystalised after standing overnight at r.t. and was collected in abuchner funnel and dried under high vacuum. Yield 19.8 g (37.5%, 46.9mmol). ¹H NMR (400 MHz, D₂O) d 7.36 (d, J=8.2 Hz, 4H), 7.53 (d, J=8.2Hz, 4H); ¹³C NMR (100 MHz, D²O) d 126.47 (+), 127.04 (+), 140.07(C_(quart)), 141.38 (C_(quart)).

[0115] (ii) Synthesis of 4,4′-Disulfanediyl-bis-benzene SulfonylChloride. (CB3.012)

[0116] A flask (100 ml) with reflux condenser and a bubbler was chargedwith CB3.011 (10 g, 23.7 mmol), POCl₃ (10 ml) and PCl5 (5 g). Themixture was heated to reflux for 2 hours (120° C. oil bath temperature).After cooling to room temperature temperative dichloromethane (50 ml)was added and the resulting mixture was poured into ice. After 1 hour ofintensive stirring the organic layer was separated and stirred withconc. bicarbonate solution (100 ml) for another hour. The organic layerwas separated again, dried over sodium sulfate and concentrated to avolume of ca. 25 ml. The product was precipitated by slow addition ofcyclohexane with stirring, filtered off and dried under high vacuum.Yield 6.89 g (16.6 mmol, 70%). m.p. 139° C. (Lit.^(Ref1): 142° C.); ¹HNMR (400 MHz, CDCl₃) d 7.69 (d, J=8.6 Hz, 4H), 7.98 (d, J=8.6 Hz, 4H);¹³C NMR (100 MHz, CDCl₃) d 126.69 (+), 128.08 (+), 143.03 (C_(quart)),145.05 (C_(quart)); MS (+FAB(3-NBA)) m/e 413.9 (100, M).

[0117] (iii) Synthesis of (CB3.010)

[0118] To a solution of (S,S)-diphenylethylenediamine (3.73 g, 17.6mmol) and triethylamine (5 ml) in 50 ml of dichloromethane a solution of4,4′-Disulfanediyl-bis-benzenesulfonyl chloride (CB3.012) (3.32 g, 8.0mmol) in dichloromethane (10 ml) was added slowly at 0° C. (ice-bath).The reaction mixture was stirred for 12 hours at room temperature andthen concentrated under reduced pressure. The crude product was purifiedby chromatography on silica (first DCM, then DCM/methanol 25:1 aseluent). The product was obtained as a slightly yellow solid. Yield 5.65g (7.37 mmol, 92%). m.p. 108-110° C.; ¹H NMR (400 MHz, CDCl₃) d 4.16 (d,J=5.3 Hz, 2H), 4.44 (d, J=5.3 Hz, 2H), 7.07-7.14 (m, 20H), 7.20 (d,J=8.8 Hz, 4H), 7.35 (d, J=8.8 Hz, 4H); ¹³C NMR (100 MHz, CDCl₃) d 60.61(+), 63.73 (+), 126.18 (+), 126.80 (+), 127.20 (+), 127.66 (+), 127.72(+), 127.81 (+), 128.48 (+), 128.64 (+), 138.92 (C_(quart)), 139.29(C_(quart)), 141.05 (C_(quart)), 141.12 (C_(quart)); MS (+FAB(3-NBA))m/e 767 (47, M+1), 106 (100); [a]D²⁰ −87.0° (c=1.31, EtOH).

[0119] (iv) Synthesis of Sodium (1S,2S)-1,2-diphenylethylenediamine-N-phenylsulfonyl-4-sulfonate (CB3.016).

[0120] CB3.016: Sodium hydroxide solution (10 ml, 2.5M in water, 25mmol) and hydrogen peroxide solution (5 ml, 27.5% by weight in water)were added a solution of CB3.010 (4.82 g, 6.28 mmol) in methanol (50ml). An exothermic reaction resulted. The resulting mixture was stirredfor 2 hours before another 2 ml or hydrogen peroxide solution wereadded. Stirring at room temperature was continued for 12 hours, thenconcentrated sodium hydrogen sulfite solution was added (10 ml) and themixture was stirred for another 2 hours. The reaction mixture wasconcentrated to dryness under reduced pressure, water (50 ml) was addedto dissolve the inorganic salts and the product was filtered off. Theproduct was washed with cold water (100 ml) and dichloromethane (50 ml)and dried under high vacuum. Yield 4.454 g (10.3 mmol, 82%). m.p.>280°C. (dec.); ¹H NMR (400 MHz, DMSO-d₆) d 4.43 (d, J=10.4 Hz, 1H), 4.65 (d,J=10.4 Hz, 1H), 6.79-6.93 (m, 5H), 7.19 (s, 5H), 7.41 (d, J=8.6 Hz, 2H),7.45 (d, J=8.6 Hz, 2H), 8.61 (bs, 4H); ¹³C NMR (100 MHz, DMSO-d₆) d59.24 (+), 62.10 (+), 126.35 (+), 126.72 (+), 128.25 (+), 128.39 (+),128.93 (+), 129.02 (+), 129.40 (+), 134.61 (C_(quart)), 136.14(C_(quart)), 141.05 (C_(quart)), 152.03 (C_(quart)); MS (FAB(3-NBA)) m/e433.1 (93, M+1), 165.0 (100); [a]D²⁰ −76.9° (c=1.3, DMSO).

Example LS2 Preparation of Sodium (1R,2R)-1,2-diaminocyclohexyl-N-phenylsulfonyl-4-sulfonate (CB3.019).

[0121]

[0122] (i) Synthesis of CB 3.018.

[0123] To solution of (R,R)-1,2-diaminocyclohexane (1.76 g, 15.4 mmol)and triethylamine (5 ml) in 50 ml of dichloromethane was added slowly asolution of 4,4′-Disulfanediyl-bis-benzenesulfonyl chloride (CB3.012)(2.91 g, 7.0 mmol) in dichloromethane (10 ml) at −78° C. (acetone/dryice bath). The reaction mixture was allowed to warm up to roomtemperature stirred for 12 hours at this temperature and thenconcentrated under reduced pressure. The crude product was purified bychromatography on silica (first DCM, then DCM/methanol 5:1 as eluent).The product was obtained as a slightly yellow solid. Yield 3.44 g (6.02mmol, 86%). m.p. 125-128° C.; ¹H NMR (400 MHz, CD₃OD) d 1.01-1.34 (m,10H), 1.53-1.65 (m, 4H), 1.86-1.98 (m, 2H), 2.35-2.45 (m, 2H), 2.74-2.82(m, 2H), 7.69 (d, J=8.6 Hz, 4H), 7.84 (d, J=8.6 Hz, 4H); ¹³C NMR (100MHz, CD₃OD) d 25.49 (−), 26.13 (−), 33.05 (−), 33.79 (−), 55.77 (+),60.31 (+), 127.84 (+), 128.70 (+), 141.94 (C_(quart)), 142.62(C_(quart)); MS (FAB(3-NBA)) m/e 571 (100, M+1); [a]D²⁰ +36.5° (c=2.0,EtOH).

[0124] (ii) Synthesis of Sodium (1R,2R)-1,2-diaminocyclohexyl-N-phenylsulfonyl-4-sulfonate (CB3.019).

[0125] Sodium hydroxide solution (4 ml, 1M in water, 4 mmol) andhydrogen peroxide solution (2 ml, 27.5% by weight in water) were addedto a solution of CB3.018 (1.142 g, 2.0 mmol) in methanol (20 ml). Anexothermic reaction ensued. The resulting mixture was stirred for 2hours before another 2 ml hydrogen peroxide solution were added.Stirring at room temperature was continued for 12 hours, thenconcentrated sodium hydrogen sulfite solution was added (5 ml) and themixture was stirred for another 2 hours. The reaction mixture wasconcentrated to dryness under reduced pressure, water (20 ml) was addedto dissolve the inorganic salts and the product was filtered off. Theproduct was washed with cold water (40 ml), ethanol (20 ml),dichloromethane (50 ml) and dried under high vacuum. Yield 883 mg (2.64mmol, 66%). m.p.>300° C.; ¹H NMR (400 MHz, DMSO-d₆) d 0.90-1.38 (m, 7H),1.84-1.98 (m, 1H), 2.66-2.82 (m, 1H), 2.88-3.02 (m, 1H), 7.82 (s, 4H),7.89 (bs, 4H); ¹³C NMR (100 MHz, DMSO-d₆) d 23.80 (−), 24.69 (−), 29.95(−), 31.21 (−), 54.22 (+), 55.62 (+), 126.90 (+), 127.17 (+), 142.00(C_(quart)), 152.54 (C_(quart)), MS (−FAB(3-NBA)) m/e 333 (100, M−1);[a]D₂₀ +21.5° (c=1.7, DMSO).

Example LS3 Preparation of Sodium (1S,2S)-1,2-diphenylethylenediamine-N-phenylsulfonyl-2-sulfonate (3.022).

[0126]

[0127] Benzene-1,2-disulfonic acid anhydride (1.30 g, 5.9 mmol) wasadded to a solution of (S,S)-diphenylethylenediamine (1.25 g, 5.9 mmol)in 150 ml of dichloromethane at room temperature. The reaction mixturewas stirred for 1 hour and then concentrated under reduced pressure.Isopropanol (50 ml) was added to the residue and the mixture heated toreflux for 15 minutes. After cooling to room temperature the productprecipitated and was collected in a sinter-funnel and washed withisopropanol (50 ml). The product is dried under high vacuum at 60° C.for 12 hours. Yield 1.96 g (4.54 mmol, 77%). m.p.>250° C.; ¹H NMR (400MHz, d6-DMSO) d 4.60 (d, J=11.9 Hz, 1H), 4.69 (dd, J=11.9, 8.2 Hz, 1H),6.71-6.79 (m, 5H), 7.12 (dt, J=7.8, 1.2 Hz, 1H), 7.16-7.19 (m, 5H), 7.35(dt, J=7.8, 1.2 Hz, 1H), 7.43 (dd, J=7.8, 1.2 Hz, 1H), 7.43 (dd, J=7.8,1.2 Hz, 1H), 7.83 (dd, J=7.8, 1.2 Hz, 1H), 8.66 (s, 3H), 8.88 (d, J=8.2Hz, 1H); ¹³C NMR (100 MHz, d6-DMSO) d 60.61 (+), 63.73 (+), 126.18 (+),126.80 (+), 127.20 (+), 127.66 (+), 127.72 (+), 127.81 (+), 128.48 (+),128.64 (+), 138.92 (C_(quart)), 139.29 (C_(quart)), 141.05 (C_(quart)),141.12 (C_(quart)); MS (+FAB(3-NBA)) m/e 767 (47, M+1), 106 (100);[a]D²⁰ −87.0° (c=1.31, EtOH).

Example LS4 Synthesis of Sodium (1R, 2R)-1,2-diphenylethylenediamine-N-phenylsulfonyl-4-sulfonate (TT-CB4).

[0128]

[0129] The preparation of TT-CB4 was undertaken in an identical mannerto CB3.016 (Example LS1) but using R,R-diphenylethylenediamine in placeof S,S-diphenylethylenediamine.

[0130] Catalyst Preparation and Hydrogenation Section.

[0131] Unless otherwise stated, the following procedures were employedfor each of Examples TH5-TH19 below.

[0132] (a) Catalyst Preparation

[0133] In a Schlenk flask (25 ml) with a magnetic stirring-bar asolution of KOt-Bu in isopropanol (0.8 ml of a 0.1 M solution, 0.08mmol) was added to a suspension of ligand (0.08 mmol) in water (1 ml)and stirred under N₂-atmosphere at room temperature until a clearsolution was obtained. To this solution the transition metal compound(0.01 mmol) was added and the mixture stirred under an argon atmosphereat 40° C. for two hours.

[0134] (b) Hydrogenation

[0135] After cooling of the solution obtained in (i) to 22° C. thesubstrate to be hydrogenated (2 mmol) in isopropanol (10 ml) and KOt-Buin isopropanol (2.0 ml of a 0.1 M solution, 0.20 mmol) were added tostart the reaction.

[0136] Samples were taken out of the reaction mixture at various timesand analysed by gas chromatography (β-dex column).

[0137] The ligand, transition metal compound and hydrogenation substrateused are tabulated below for each Example together with the resultsobtained in the hydrogenation reaction.

Example TH5

[0138] This Example demonstrates ruthenium catalysed asymmeterictransfer hydrogenation of acetophenone in accordance with the equation:

[0139] The reagents used were as follows Transition Metal[RuCl₂(p-cymene)]₂  6.1 mg Compound Ligand CB3.016 34.6 mg HydrogenationSubstrate Acetophenone  240 mg

[0140] The results are shown in Table 1. TABLE 1Ruthenium/CB3.016/acetophenone. Hydrogenation at 22° C. Time [h] T [°C.] Conversion [%] ee [%]  3 22 16 95.0 20 22 61 95.3 28 22 74 95.3 4422 96 94.4

Example TH6

[0141] Example TH5 was repeated save that in step (a) stirring waseffected at 22° C. (rather than 40° C.) and that step (b) was carriedout at temperatures of 22° C., 30° C. and 40° C.

[0142] The results are shown in Tables 2 to 4. TABLE 2Ruthenium/CB3.016/Acetophenone Hydrogenation at 22° C. Time [h] T [° C.]Conversion [%] ee [%] 1 22 3 — 2 22 7 — 3 22 10 — 4 22 13 — 16 22 3996.3 25 22 51 95.3 41 22 58 96.3 69.5 22 62 96.0

[0143] TABLE 3 Ruthenium/CB3.016/Acetophenone at 30° C. Time [h] T [°C.] Conversion [%] ee [%] 1 30 10 95.0 2 30 19 — 3 30 26 — 4 30 34 95.716 30 68 95.2 25 30 73 95.5 41 30 77 95.1 69.5 30 77 94.2

[0144] TABLE 4 Ruthenium/CB3.016/Acetophenone at 40° C. Time [h] T [°C.] Conversion [%] ee [%] 1 40 31 95.2 2 40 48 94.4 3 40 58 95.6 4 40 6694.6 16 40 89 94.2 25 40 90 93.7 41 40 92 93.5 69.5 40 91 93.4

[0145] The temperature-effect is significant, but in all cases aslowdown or standstill of the reaction after about 20 h was observed,probably due to precipitation of the catalyst.

[0146] The drop in enantioselectivity was not as high as expected.

Example TH7

[0147] This Example demonstrates the rhodium catalysed transferhydrogenation of acetophenone using CB3.016 as a ligand for thecatalyst.

[0148] The following reactants were employed. Transition Metal Compound¹Rh(Cp*)Cl₂]₂ Ligand CB3.016 Hydrogenation Substrate Acetophenone

[0149] The results obtained are shown in Table 5. TABLE 5Rhodium/CB3.016/Acetophenone Time [h] T [° C.] Conversion [%] ee [%]  122 34 97 18 22 72 97

Example TH8

[0150] This Example demonstrates the ruthenium catalysed transferhydrogenation of acetophenone using CB3.019 as catalyst ligand.

[0151] The following reactants were used. Transition Metal Compound[RuCl₂(p-cymene)]₂ Ligand CB3.019 Hydrogenation Substrate Acetophenone

[0152] The results are shown in Table 6 TABLE 6Ruthenium/CB3.019/Acetophenone Time [h] Conversion [%] ee [%] 1  1 —19.5 28 88.0 28 40 90.7 51 54 90.8 96 67 89.8

Example TH9

[0153] This Example demonstrates the rhodium catalysed transferhydrogenation of acetophenone using CB3.019 as catalyst ligand.

[0154] The following reactants were used. Transition Metal Compound[Rh(Cp*)Cl₂]₂ Ligand CB3.019 Hydrogenation Substrate Acetophenone

[0155] The results are shown in Table 7 TABLE 7Rhodium/CB3.019/Acetophenone. Time [h] Conversion [%] ee [%] 1 62 97.619.5 94 94.9 28 94 94.5 51 94 94.6 96 96 94.5

[0156] Comparing the results of Examples TH8 and TH9, therhodium-catalysed system proved to be more reactive and selectivecompared to the ruthenium one. The enantioselectivity was close to 98%after 1 h and dropped slightly at the end to 94.5%.

Example TH10

[0157] This Example investigates the use of a catalysts based onruthenium and either CB3.016, CB3.019 or CB.022 in the hydrogenation ofa range of aromatic ketones as hydrogenation substrate. Thehydrogenation procedure used was as described previously save that 1 cm³of water was added additionally to the isopropanol and KOt-By. The waterconcentration was thus 15%.

[0158] The following reactants were used Transition Metal Compound[RuCl₂(p-cymene)]₂ Ligand (1) CB3.016 Ligand (2) CB-3.019 Ligand (3)CB3.022 Hydrogenation Substrate (5)-(10) See below

[0159] The results are shown in Table 8. TABLE 8 Ruthenium/CB3.016(1) orCB3.019(2) or CB3.022(3)/Ketones(5)-(10). Reaction time ConversionKetone Ligand [h] [%] Ee [%] 5 1 48 96 94 5 2 48 91 88 5 3 48 11 91 6 14 100 81 6 2 4 100 88 7 1 24 90 87 7 2 24 91 81 8 1 18 10 24 8 2 18 1855 9 1 42 31 91 9 2 42 35 83 10 1 72 94 95 10 2 48 87 90

Example TH11

[0160] Example TH10 was repeated but using [Rh(Cp*)Cl₂]₂ as thetransition metal compound. Thus, the reactants were as follows:Transition Metal Compound [Rh(Cp*)Cl₂]₂ Ligand (1) TT-CB4 Ligand (2)CB3.019 Hydrogenation Substrate (5)-(10) See above

[0161] The results are shown in Table 9. TABLE 9 Rhodium/TT-CB4(1) orCB3.019(2)/Ketones(5)-(10) Reaction time Conversion Ketone Ligand [h][%] ee [%] 5 1 24 92 97 5 2 18 94 95 6 1 4 100 83 6 2 2 100 88 7 1 18 9895 7 2 4 99 94 8 1 18 2 22 8 2 18 40 76 9 1 42 9 94 9 2 42 65 95 10 1 6481 82 10 2 48 95 96

[0162] The results in tables 8 and 9 show the effectiveness of TT-CB4and CB3.019 in transfer hydrogenations. p-Trifluoromethyl acetophenone(6) reacts rapidly and quantitatively giving moderate and very similaree's in the ruthenium and rhodium catalysed reaction. m-Trifluoromethylacetophenone (7) reacts slightly more slowly giving a very high ee onlyin the rhodium catalysed reaction. o-Trifluoromethyl acetophenone (8)reacts very slowly, compared to (6) and (7). Only the rhodium-catalysedreaction using ligand (2) shows moderate enantioselectivity. Theelectron-rich p-methoxy acetophenone (9) reacts relatively slowly, asexpected. It was not possible to obtain a conversion above 65% underthese conditions. 2-Acetylnaphthalene (10) reacts similarly toacetophenone.

Example TH12

[0163] The Example demonstrates the ruthenium catalysed transferhydrogenation of acetophenone using TT-CB4 as catalyst ligand.Transition Metal Compound [RuCl₂(p-cymene)]₂ Ligand TT-CB4Hydrogeneration Substrate Acetophenone

[0164] The results are shown in Table 10. TABLE 10Ruthenium/TT-CB4/Acetophenone Reaction Time (hours) Conversion *(%)Enantiomeric excess (%) 19 30 94.4 24.5 34 95.0 42.5 46 94.4 49 48 94.266 55 94.4 73 58 94.3 90 62 94.4 96 64 94.4

Example TH13

[0165] Example TH12 was repeated using 4-Bromoacetophenone ashydrogenation substrate in place of acetophenone.

[0166] The following reactants were employed. Transition Metal Compound[RuCl₂(p-cymene)]₂ Ligand TT-CB4 Hydrogenation Substrate4-Bromoacetophenone

[0167] The results shown in Table 11 TABLE 11Ruthenium/TT-CB4/4-Bromoacetophenone Reaction Time (hours) Conversion(%) Enantiomeric excess (%) 20.5 43 92.4 27 51 92.4 44 67 92.3 50.5 7392.4 67.5 82 92.3 73.5 85 92.3 139 98 92.1

Example TH14

[0168] Example TH13 was repeated but using 2-Fluoroacetophenone ashydrogenation substrate.

[0169] The following reactants were employed. Transition Metal Compound[RuCl₂(p-cymene)]₂ Ligand TT-CB4 Hydrogenation Substrate2-Fluoroacetophenone

[0170] The results are shown in Table 12. TABLE 12Ruthenium/TT-CB4/2-Fluooacetophenone Reaction Time (hours) Conversion(%) Enantiomeric excess (%) 2 7 73.3 19 41 75.1 26 48 75.1 43 64 75.048.5 69 75.3 114.5 91 75.2

[0171] Comparing the results of Examples TH12 to TH14, it can be seenthat the rates of these reactions are generally quite low. However, thepresence of an electron-withdrawing group 2-fluoroacetophenone increasesthe rate of reaction. The enantioselectivities are high except in thecase of the reduction of 2-fluoroacetophenone. This result is notsurprising given that the fluoro substituent is in the ortho position.It can also be seen that the enantiomeric excess does not decrease overtime as would be expected.

Example TH15

[0172] This Example describes the iridium catalysed hydrogenation ofacetophenone using TT-CB4 as catalyst ligand. The hydrogenationprocedure used was the same as that of Example TH10 (15% water)

[0173] The following reactants were employed. Transition Metal Compound¹[Ir(Cp)Cl₂]₂ Ligand TT-CB4 Hydrogenation Substrate (a)-(k) See below ¹[Ir(pentamethylcyclopentadienyl)₂Cl₂]₂

a: R═H b: R═F h: R═CF₃

c: R═Cl d: R═Br i: R═OMe

e: R═F f: R═Br g: R═Cl

j

k

[0174] The results are shown in Table 13. TABLE 13Iridium/TT-CB4/ketones (a)-(k) Ketone Reaction Time (h) Conversion (%)Ee (%) a 140 90 82 b 51 83 85 c 91 89 76 d 91 93 76 e 68 86 36 F 163 6529 G 163 89 24 H 43 95 86 I 150 22 78 J 139 41 91 K 139 77 73

Example TH16

[0175] Example TH15 was repeated but using CB-3.019 as ligand in placeof TT-CB4.

[0176] The following reactants were employed. Transition Metal Compound[Ir(Cp*)Cl₂]₂ Ligand CB-3.019 Hydrogenation Substrate Ketones (a)-(k)

[0177] The results are shown in Table 14 TABLE 14Iridium/CB-3.019/ketones (a)-(k). Ketone Reaction Time (h) Conversion(5) ee(%) a 26 88 96 b 26 99 94 c 25 98 94 d 20 99 95 e 21 99 73 f 92 9566 g 46 96 63 h 4 98 93 i 141 80 95 j 45 55 97 k 45 96 96

[0178] There are noticeable differences in the results obtained forruthenium and iridium with ligand 1 (TT-CB4). Generally, the rutheniumsystem gives rise to higher enantiomeric excess and lower reaction rate,whereas the iridium system gives a higher reaction rate and a lowerenantiomeric excess. However, the combination of iridium and ligand 2proved to be most successful. The reactions tended to proceed rapidlywith high enantioselectivity. For all systems, electron deficientketones were reduced more quickly. This is best illustrated by comparingthe results of the reduction of 3-trifluoromethylacetophenone and4-methoxyacetophenone. Also, as expected, substrates with ortho-groupsgave rise to a lower reactivity and enantiomeric excess.

Example TH17

[0179] In order to determine the effect of an increase in waterconcentration, the procedures of Examples TH14 and 15 were repeated butusing a 2-propanol-water mixture containing (i) 34% and (ii) 51% water.The overall volume of reaction solvent remained unchanged.

[0180] The following reactants were employed. Transition Metal Compound[Ir(Cp*)Cl₂]₂ Ligand (1) TT-CB4 Ligand (2) CB-3.019 HydrogenationSubstrate Ketones (a)-(k)

[0181] The results are shown in Table 15. TABLE 15 Iridium/TT-CB4(1) orCB3.019(2)/Ketones (a)-(k) Reaction Conversion Ketone Ligand Time(h) (%)ee(%) b^(i) 1 22 74 92 b^(ii) 1 22 90 92 b^(i) 2 2.5 82 94 b^(ii) 2 2.594 93 e^(ii) 2 5 97 74 i^(i) 1 115 20 84 i^(ii) 1 115 33 91 i^(i) 2 11676 92 i^(ii) 2 116 89 87 k^(i) 1 42 47 91 k^(ii) 1 42 66 93 k^(i) 2 1892 95 k^(ii) 2 18 92 94

[0182] Table 3. Iridium systems containing (i) 34% and (ii) 51% water.

[0183] The results shown in Table 15 are surprising in that in expectedrate decrease relating to the lower concentration of 2-propanol was notobserved. Instead, a significant rate increase was noted for both the(i) 34% and (ii) 51% water systems. In addition to this, iridium-ligand1 systems showed a large increase in enantiomeric excess when theconcentration of water was increased form 15% to 34% (see F resultsshown in Table 13.).

Example LS18

[0184] This Example demonstrates the synthesis of a further ligand:

Example TH19

[0185] Bis-3,5-trifluoromethylacetophenone (1.32 g, 5.16 mmoles),dichloro(pentamethylcyclopentadienyl)rhodium(III) dimmer (7.4 mg, 11.97micromoles), sodium (1S,2S)4-(2-Amino-1,2-diphenyl-ethylsulfamoyl)-benzenesulfonate (11.2 mg, 25.92micromoles), and 2.5 ml tetrahydrofuran were charged to a 25 ml flaskand flushed with nitrogen. Water (12 microlitres, 0.66 mmoles) was addedby syringe and the mixture was stirred for 20 minutes. A 2:5 molar ratiomixture of triethylamine and formic acid were added to the reaction at arate of 1.5 ml/h for 2 h. At this time all the ketone had been convertedto alcohol and the optical purity was determined to be 81% ee. Thereaction was concentrated by vacuum distillation a sample A was takenfor Rhodium analysis. To the concentrate, 3 ml toluene and 5 ml waterwas added, the aqueous phase separated and the organic layer dividedinto three portions B, C, D of 1 ml. To each portion was added 1.6 mlwater. Sample B was concentrated to dryness. To sample C 100 mg ofAmberlite™ IRA-93 was added and the mixture stirred for 2 hours,filtered and the filtrate concentrated to dryness. To sample D 100 mg ofDowex™ 1×8−50 was added and the mixture stirred for 2 hours, filteredand the filtrate concentrated to dryness. In sample B the concentratedfiltrate was dark purple, whilst in samples C and D it was a light pink.

[0186] The samples were analysed by ICPMS for Rhodium and the followingresults were obtained: Sample A 4930 ppm Sample B 1040 ppm Sample C  365ppm Sample D  280 ppm

[0187] The results from the analysis of Samples C and D compared toSample B show that treatment of the reaction mixture with ion exchangeresins is effective in the separation of the catalyst from the reactionmixture.

1. A process for the transfer hydrogenation of an organic compoundhaving a carbon-carbon or carbon-heteroatom double bond, said processcomprising reacting the organic compound with a hydrogen donor in thepresence of a catalyst having the general formula:

in which: R¹⁸ represents an optionally substituted hydrocarbyl orperhalogenated hydrocarbyl ligand; A represents —NR¹⁹—, —NR²⁰—, —NHR¹⁹,—NR¹⁹R²⁰ or —NR²⁰R²¹ where R¹⁹ is H, C(O)R²¹, SO₂R²¹, C(O)NR²¹R²⁵,C(S)NR²¹R²⁵, C(═NR²⁵)SR²⁶ or C(═NR²⁵)OR²⁶, R²⁰ and R²¹ eachindependently represents an optionally substituted hydrocarbyl,perhalogenated hydrocarbyl or an optionally substituted heterocyclylgroup, and R²⁵ and R²⁶ are each independently hydrogen or a group asdefined for R²¹; represents —O—, —OH, OR²², —S—, —SH, SR²², —NR²²—,—NR²³—, —NHR²³, —NR²²R²³, —NR²²R²⁴, —PR²²— or —PR²²R²⁴ where R²³ is H,C(O)R²⁴, SO₂R²⁴, C(O)NR²⁴R²⁷, C(S)NR²⁴R²⁷, C(═NR²⁷)SR²⁸ or C(═NR²⁷)OR²⁸,R²² and R²⁴ each independently represents an optionally substitutedhydrocarbyl, perhalogenated hydrocarbyl or an optionally substitutedheterocyclyl group, and R²⁷ and R²⁸ are each independently hydrogen or agroup as defined for R²⁴; E represents a linking group; M represents ametal capable of catalysing transfer hydrogenation; and Y represents ananionic group, a basic ligand or a vacant site; provided that when Y isnot a vacant site that at least one of A or B carries a hydrogen atom,characterised in that at least one of said groups R²⁰ to R²² or R²⁴ toR²⁸ is present in the form of an optionally substituted sulphonatedhydrocarbyl group, a sulphonated perhalogenated hydrocarbyl group, or anoptionally substituted sulphonated heterocyclyl group.
 2. A processaccording to claim 1 wherein M is a group VIII transition metal,especially ruthenium, rhodium or iridium.
 3. A process according toclaim 1 or 2 in which A-E-B is, or is derived from, an aminoalcohol or adiamine carrying on an or the amino nitrogen atom a substituentincorporating a group R²⁰ to R²² or R²⁴ to R²⁸ in the form of anoptionally substituted sulphonated hydrocarbyl group, a sulphonatedperhalogenated hydrocarbyl group or an optionally substitutedsulphonated heterocyclyl group.
 4. A process according to claim 3wherein E has 2, 3 or 4 carbon atoms linking A and B, said carbon atomsoptionally carrying one or more substituents.
 5. A process according toclaim 4 wherein E is of the formula —CHR³⁰—CHR³¹— where R³⁰ and R³¹ areindependently hydrogen or an optionally substituted hydrocarbyl group.6. A process according to claim 4 wherein E has two carbon atoms linkingA and B and is a bond in an optionally substituted cycloaliphatic ring.7. A process according to any one of claims 1 to 6 wherein A is a groupof the formula —NHR¹⁹ or —NR¹⁹— where R¹⁹ is represented by the group—SO₂R²¹ in which R²¹ is an optionally substituted sulphonatedhydrocarbyl group, sulphonated perhalogenated hydrocarbyl group oroptionally substituted sulphonated heterocyclyl group.
 8. A processaccording to claim 7 wherein R²¹ is a sulphonated phenyl group having nsulphonate groups where n is 1 to
 5. 9. A process according to claims 7or 8 wherein B is —NH₂ or —NH—.
 10. A process according to any one ofclaims 1-9 wherein R¹⁸ is an optionally substituted aryl or anoptionally substituted alkene.
 11. A process according to claim 10wherein R¹⁸ is cymene.
 12. A process according to claim 10 wherein R¹⁸is a pentamethylcyclopentadienyl group.
 13. A process according to anyone of claims 1 to 12 wherein the organic compound to be hydrogenated isa ketone, an amine or an iminium salt.
 14. A process as claimed in anyone of claims 1 to 12 wherein the organic compound to be hydrogenated isof formula (I):

wherein: X represents O, S, CR³R⁴, NR⁵, (NR⁶R⁷)⁺Q⁻, N⁺R⁸—O⁻,(NR⁹OR¹⁰)⁺Q⁻, NNR¹²R¹³, NNR¹²SO₂R¹⁶, NNR¹²COR¹⁷, (NR¹¹NR¹²R¹³)⁺Q⁻,(NR¹¹NR¹²C(═NR¹⁴)R¹⁵)⁺Q⁻, (NR¹¹NR¹²SO₂R¹⁶)⁺Q⁻, (NR¹¹NR¹²COR¹⁷)⁺Q⁻,NP(O)R¹⁵R¹⁶, NS(O)R¹⁵ or NSO₂R¹⁵. Q⁻ represents a monovalent anion; R¹,R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ R¹², R¹³ and R¹⁴ eachindependently represents a hydrogen atom, an optionally substitutedhydrocarbyl, a perhalogenated hydrocarbyl or an optionally substitutedheterocyclyl group, one or more of R¹ and R², R¹ and R³, R¹ and R⁵, R¹and R⁶, R¹ and R⁸, R¹ and R⁹, R¹ and R¹¹, R¹ and R¹², R² and R⁴, R² andR⁷, R² and R¹⁰, R³ and R⁴, R⁶ and R⁷, R⁹ and R¹⁰, R¹¹ and R¹², and R¹²and R¹³ optionally being linked in such a way as to form an optionallysubstituted ring(s); and R¹⁵, R¹⁶ and R¹⁷ each independently representsan optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl oran optionally substituted heterocyclyl group;
 15. A process as claimedin any one of claims 1 to 14 wherein the organic compound to behydrogenated is prochiral and the catalyst is chiral, an enatiomericallyand/or diastereomerically purified form of the catalyst being employed,whereby the organic compound is asymmetrically hydrogenated.
 16. Aprocess according to claim 15 in which A-E-B comprises at least onestereo specific centre.
 17. A process according to any one of claim 1 to16 in which the hydrogen donor is selected from hydrogen, primary andsecondary alcohols, primary and secondary amines, carboxylic acids andtheir esters and amine salts, readily dehydrogenatable hydrocarbons,clean reducing agents, and any combination thereof.
 18. A processaccording to claim 17 wherein the hydrogen donor is isopropanol.
 19. Aprocess according to any one of claims 1 to 18 wherein the process iscarried out in the presence of a base having pK_(a) of at least 8.0. 20.A process as claimed in any one of claims 1 to 19 wherein the catalystis used in the form a supported liquid phase catalyst.
 21. A process asclaimed in any one of claims 1 to 19 which comprises an additional stepof adding an ion exchange resin after reacting the organic compound withthe hydrogen donor in the presence of the catalyst.
 22. A catalysthaving the general formula:

in which: R¹⁸ represents an optionally substituted hydrocarbyl orperhalogenated hydrocarbyl ligand; A represents —NR¹⁹—, —NR²⁰—, —NHR¹⁹,—NR¹⁹R²⁰ or —NR²⁰R²¹ where R¹⁹ is H, C(O)R²¹, SO₂R²¹, C(O)NR²¹R²⁵,C(S)NR²¹R²⁵, C(═NR²⁵)SR²⁶ or C(═NR²⁵)OR²⁶, R²⁰ and R²¹ eachindependently represents an optionally substituted hydrocarbyl,perhalogenated hydrocarbyl or an optionally substituted heterocyclylgroup, and R²⁵ and R²⁶ are each independently hydrogen or a group asdefined for R²¹; B represents —O—, —OH, OR²², —S—, —SH, SR²², —NR²²—,—NR²³—, —NHR²³, —NR²²R²³, —NR²²R²⁴, —PR²²— or —PR²²R²⁴ where R²³ is H,C(O)R²⁴, SO₂R²⁴, C(O)NR²⁴R²⁷, C(S)NR²⁴R²⁷, C(═NR²⁷)SR²⁸ or C(═NR²⁷)OR²⁸,R²² and R²⁴ each independently represents an optionally substitutedhydrocarbyl, perhalogenated hydrocarbyl or an optionally substitutedheterocyclyl group, and R²⁷ and R²⁸ are each independently hydrogen or agroup as defined for R²⁴; E represents a linking group; M represents ametal capable of catalysing transfer hydrogenation; and Y represents ananionic group, a basic ligand or a vacant site; provided that when Y isnot a vacant site that at least one of A or B carries a hydrogen atom,characterised in that at least one of said groups R²⁰ to R²² or R²⁴ toR²⁸ is present in the form of an optionally substituted sulphonatedhydrocarbyl group, a sulphonated perhalogenated hydrocarbyl group, or anoptionally substituted sulphonated heterocyclyl group.
 23. A catalyst asclaimed in claim 22 which is as further defined in any one of claims 2to
 9. 24. A catalyst as claimed in claim 22 or 23 in which the catalystis prochiral, and resolved forms thereof.
 25. A catalyst as claimed inclaim 24, in which A-E-B comprises at least one stereospecific centre.26. A process for the preparation of a catalyst according to any one ofclaims 22 to 25 which comprises reacting a metal aryl halide complex ora metal alkenyl halide complex with a compound of formula A-E-B or aprotonated equivalent from which it may be derived.
 27. A ligand fromwhich a compound A-E-B is derived having the following formula:

in which: W represents —OH or —NH₂; R³² represents an aryl group havingat least one —SO₃H or —SO₃M¹ substituent and is further optionallysubstituted. R³³, R³⁴ are independently optionally substitutedhydrocarbyl groups or R³³ and R³⁴ are optionally linked in such a way asto define an optionally substituted ring.
 28. A ligand according toclaim 27 in which R³² is a phenyl group having one —SO₃H or —SO₃M¹substituent.
 29. A ligand according to claim 27 or 28 in which R³³ andR³⁴ are independently phenyl.
 30. A ligand according to claim 27, 28 or29 in which R³³ and R³⁴ are linked so as to define a cyclohexyl ring.31. The compound:

and salts thereof.
 32. The compound:

and salts thereof
 33. The compound:

and salts thereof.
 34. The compound:

and salts thereof.
 35. A process comprising reacting a di-sulphide offormula:

with an oxidant to produce a compound of formula:

wherein: W is —OH or —NH₂; R³² is an aryl group having at least one—SO₃H or SO₃M¹ (M¹=alkali metal) substituent; R³⁵ is an aryl group; andR³³, R³⁴ are independently optionally substituted hydrocarbyl groups orR³³ and R³⁴ are optionally linked in such a way as to define anoptionally substituted ring, more preferably R³³ and R³⁴ areindependently phenyl or R³³ and R³⁴ are linked so as to define acyclohexyl ring.
 36. A process according to claim 35 wherein thesubstitution pattern of the aryl group R³² is such that the —SO₃H orSO₃M¹ (M¹=alkali metal) substituent is positioned para with respect tothe SO₂NH—CHR³⁴—CHR³³—W group.
 37. A process according to claim 35 or 36wherein the oxidant is alkaline hydrogen peroxide, preferably a mixtureis sodium hydroxide solution and hydrogen peroxide solution.